This competing continuation application focuses on neural mechanisms in entorhinal cortex that could underlie coding of space and time in episodic memory. This includes testing the role of cholinergic modulation of cellular properties in generating and modulating grid cell firing properties in entorhinal cortex. Research in Aim #1 will test multiple single unit recording of entorhinal grid cells before and after pharmacological infusions of drugs influencing acetylcholine levels and acetylcholine receptor activation. Experiments will test predictions from computational models of the cellular mechanisms of grid cells that predict changes in grid field accuracy and spacing during manipulations of acetylcholine levels. Research in Aim #2 will test models of the generation of grid cells and context-dependent spiking activity in the hippocampus and entorhinal cortex in a range of behavioral tasks. Experiments will test alternate versions of the model that obtain different patterns of context-dependent firing dependent on velocity, speed or time after reset by different stimuli. Research in Aim #3 will test cellular properties of currents that could underlie grid cell firing in entorhinal cortex, guided by models linking network properties of grid cells to cellular mechanisms. Studies will test whether differences in the acetylcholine sensitive M-current could underlie differences in grid cell spatial frequency along the dorsal to ventral axis of medial entorhinal cortex. Studies will also test effects of cholinergic modulation on the resonance and membrane potential oscillation frequency of entorhinal neurons to link these effects to changes in grid cell firing associated with pharmacological manipulations in behaving animals. These studies will enhance our understanding of the dynamical mechanisms in the entorhinal cortex for encoding space and time in episodic memory. This work will enhance our understanding of cellular and circuit mechanisms of disorders involving impairments and distortions of memory function, including mental disorders such as depression and schizophrenia, associated with impairments of memory and decreased volume of hippocampus and entorhinal cortex, as well as memory-related neurological disorders such as Alzheimer's disease. PUBLIC HEALTH RELEVANCE: This grant focuses on studying the brain mechanisms for storing episodes from life and retrieving these episodes at other times, based on interacting populations of neurons. This work includes experiments testing models of how cells code the spatial location of episodes and how certain drugs influence the coding by these cells. These experiments and models are relevant to brain mechanisms that may break down in disorders involving distortions of memory encoding and retrieval, including disorders such as depression, which is associated with memory impairments and a negative bias in retrieved memories, as well as schizophrenia, which involves impairments and distortions in memory function.